Ethylene oxide residues

Anderson, S.R. Ethylene oxide residues in medical materials. Bull. Parent. Drug Assoc. 1973, 27 (2), 49-58. 

The solubility of sterilising gases in polymers is important in determining the retention of residues which may, as in the case of ethylene oxide residues, be toxic. The quality control problems of polymers and plastics are considerable. Both the chemical and physical nature of the material has to be taken into account, as well as purity. 

Ethylene oxide residues remaining on products present a more complicated picture. Limits should properly be based on risk assessment. Satisfactory risk... 

Rodricks, J. V., and Brown, S. L. (1991). Ethylene oxide residues Toxicity, risk assessment, and standards. In Sterilization of Medical Products Volume V (R. F. Morrissy and Y. Prokopenko, eds.). Morin Heights, Canada Polyscience Publications. 

Figure 21.3 Effect of the nature of the oil and monomer on the percentage of surfac-tant(s) necessary for the formation of microemulsions as a function of HLB (oil to aqueous phase weight ratio 1) at 20 °C. For , A, the aqueous (diase comptis water 55%. AM 40°%, sodium acetate 5% and the oils were Isopar M, a cyclohexane, toluene. For A the aqueous phase comprised water 50%, MADQUAT 50% and the oil was cyclohexane. Suifactant(s) GCI) used were , A. polyoxyethylene sorbitol monooleate with 40 ethylene oxide residues (G 1086)+sorbitan sesquioleate (Arlacel 83) and A Soibitan monooleate with 20 ethylene oxide residues (Tween 80) + Arlacel 83 [67]...

As final product or as-used medical devices are generally made available in the sterilized state, the effect of sterilization and sterilization technique must be considered. Steam sterilization, radiation sterilization, or ethylene oxide sterilization may lead to modifications in the surface and bulk properties of the material and this may have a potential impact on the biocompatibility. Radiation sterilization may aosslink or degrade polymers leading to property changes. Ethylene oxide residuals are known to have an adverse reaction on in vitro toxicity tests. For these reasons, characterization of the final product following sterilization is necessary. 

The simultaneously occurring transacetalization then provides for a random distribution of ethylene oxide residues in the copolymers. The ethylene oxide groups terminate depolymerization of the oxymethylene chains if the depolymerizations are adventitiously started by chain scission. 

These stabilizers are not just transfer agents, however, but also copolymerization components. In the copolymerization of trioxane with, for example, ethylene oxide, the ethylene oxide is first incorporated into the copolymer quantitatively at low yields. Later, because of the simultaneously occurring transacetalization, a random distribution of the ethylene oxide residues in the copolymer results. 

The synthesis of a PEO-lipid containing a double-aliphatic C12 chain and a hydrophilic chain consisting of 13 ethylene oxide residues to which the Cl2 chains were bound was realized for the first time by Kuwamura [13] and then by Sunamoto s group [14]. The chemical structure of this PEO-lipid is shown in Fig. 1. 

L/min N2) for the characterization of alcohol (AE) and alkylphenolethoxylates (APE). The authors noted that for those APEs with a low number of ethylene oxide residues, the ELSD skews the molecular weight distribution to higher molecular weights. This is due in part to the volatility of those species (and therefore a lower than expected signal). Conversely, the UV absorptivity must be corrected for the decrease in molar absorptivity as the chain length increases. The latter fact is critical if one pure standard is used for quantitation of all components. Overall, peak shapes were excellent and the authors claimed excellent reproducibility. 

Filser JG, Kreuzer PE, Greim H, Bolt HM. New scientific arguments for regulation of ethylene oxide residues in skin-care products. Arch Toxicol 1994 68 401-405. 

It may be noted that the hydroxyethyl group itself can react with ethylene oxide so that side-chains of varying length may be present in the product. Commercial materials generally contain between 1.4 and 2.0 ethylene oxide residues per glucose residue and have a degree of substitution of about 0.8—1.0. 

Tadros [133] predicted an increase in the thickness of adsorbed polyvinyl alcohol layer at the paraffin-water interface with increasing bulk concentration from 3.5 nm at 1 ppm to 67.7 nm at 20 ppm. It is doubtful, however, whether it is possible solely on the evidence of results from application of Equation 8.35, to confirm multilayer formation. Kayes [134] has calculated using this equation, adsorbed layer thicknesses on solid particles for alkyl polyoxyethylene monoethers of 3.2 and 9.2 nm for derivatives with 30 and 60 ethylene oxide residues, respectively, which approximates to monolayer coverage. 

The Environmental Protection Agency (EPA) regulates the use and application of mixtures of ethylene oxide and carbon dioxide or halocarbon, which are used as sterilants and fumigants (7), and has established working condition limits and limit levels for allowable ethylene oxide residues in products. Ethylene oxide is also listed as a hazardous air pollutant under the flammable and toxic classes (8) by EPA s Clean Air Act. 

Of the three worldwide manufacturers of poly(ethylene oxide) resins. Union Carbide Corp. offers the broadest range of products. The primary quaUty control measure for these resins is the concentrated aqueous solution viscosity, which is related to molecular weight. Specifications for Polyox are summarized in Table 4. Additional product specifications frequendy include moisture content, particle size distribution, and residual catalyst by-product level. 

Molecular Weight. Measurement of intrinsic viscosity in water is the most commonly used method to determine the molecular weight of poly(ethylene oxide) resins. However, there are several problems associated with these measurements (86,87). The dissolved polymer is susceptible to oxidative and shear degradation, which is accelerated by filtration or dialysis. If the solution is purified by centrifiigation, precipitation of the highest molecular weight polymers can occur and the presence of residual catalyst by-products, which remain as dispersed, insoluble soHds, further compHcates purification. 

It is necessary to determine the bioburden and make cycle verification studies when ethylene oxide sterilization is used, as it is for other sterilization methods. The manufacturer of hospital sterilization equipment provides cycle recommendations based on the expected bioburden and the consideration of an appropriate safety factor. In ethylene oxide sterilization, it is necessary to determine if residues of the stefilant are absorbed by the sterilized article, and to examine the possible formation of other potentially toxic materials as a result of reaction with ethylene oxide. 

Polymers. Studies to determine possible exposure of workers to residual epichl orohydrin and ethylene oxide monomers in the polymers have been done. Tests of warehouse air where Hydrin H and Hydrin C are stored showed epichl orohydrin levels below 0.5 ppm. Air samples taken above laboratory mixing equipment (Banbury mixer and 6" x 12" mill) when compounds of Hydrin H or C were mixed gave epichl orohydrin levels below detectable limits, and ethylene oxide levels less than 0.2 ppm, well below permissible exposure limits (46). A subacute vapor inhalation toxicity study in which animals were exposed to emission products from compounded Parel 58 suggests that no significant health effects would be expected in workers periodically exposed to these vapors (47). 

Polymers with much higher average molecular weights, from 90,000 to 4 x 10 , are formed by a process of coordinate anionic polymerization (43—45). The patent Hterature describes numerous organometaUic compounds, aLkaline-earth compounds, and mixtures as polymerization catalysts. Iron oxides that accumulate in ethylene oxide storage vessels also catalyze polymerization. This leads to the formation of nonvolatile residue (NVR) no inhibitor has been found (46). 

Ethylene oxide (2.5 ml, 0.05 mole) is condensed in a 50-ml round-bottom flask containing 5 ml of methylene chloride by introducing the gas via a tube into the ice-cooled flask. To the cooled flask are added triphenylphosphine (6.6 g, 0.025 mole), benzaldehyde (2.6 g, 0.025 mole), and ethyl bromoacetate (4.2 g, 0.025 mole). The flask is closed with a drying tube, brought to room temperature, and allowed to stand overnight. Fractional distillation of the solution then yields 2-bromoethanol, bp 55717 mm followed by the desired ethyl cinnamate, bp 142-144717 mm (27171 atm) in about 90% yield. The residue consists of triphenylphosphine oxide, mp 150°. 

The two compounds were dissolved in diethyl ether by extracting the acidic layer three times with successive 500 ml portions of diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate and filtered, and the ether was removed by evaporation in vacuo. A residue consisting of 400 g of a mixture of o-chlorophenyl ethylene-/3-bromohydrin and o-chlorophenyl ethylene oxide was obtained. 

Ethyl N-phthaloyl p-aminophenylalaninate (3.15 g) (unrecrystallized) was suspended in water (50 g) and glacial acetic acid (30 g) added. To the clear solution, ethylene oxide (8.0 g) was added, the mixture allowed to stand for 17 hours, and then poured into water (350 g). The solution was neutralized with sodium hydrogen carbonate and the liberated gum extracted with ether. The ethereal solution was dried (magnesium sulfate) and eyapo-rated. The residual gum (3.95 g) was dissolved in benzene (50 g) and the solution dried azeotropically by distilling off some of the solvent. Freshly distilled phosphorus oxychloride (8 g) was added and the mixture heated under reflux for 30 minutes. 

The following procedure is given in U.S. Patent 3,458,528 78 grams (0.675 mol) of 5-nitroimidazole is dissolved in 1,500 ml of acetic acid upon the addition of 72 ml (0.57 mol) of boron trifluoride etherate. 175 ml (3.5 mols) of ethylene oxide in 175 ml of hexane, in a dropping funnel topped with a cold finger, is added slowly over 1 hour to the above solution maintained at 32° to 35°C with a water cooling bath. The mixture is concentrated under high vacuum to 100 to 150 ml volume. The residue is diluted with 500 ml of water, neutralized to pH 7 with aqueous sodium hydroxide, and extracted with 1.5 liters of ethyl acetate. The extract is dried and evaporated to yield 1-(2 -hydroxyethyl)-5-nitroimidazole. 

Paraformaldehyde/DMSO dissolves cellulose rapidly, with neghgible degradation, and forms the hydoxymethyl (methylol) derivative at Ce [ 140-142]. Therefore, cellulose derivatives at the secondary carbon atoms are easily obtained after (ready) hydrolysis of the methylol residue. Additionally, fresh formaldehyde may add to the methylol group, resulting in longer methylene oxide chains, that can be functionahzed at the terminal OH group, akin to non-ionic, ethylene oxide-based surfactants [143,144]. 

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